title: MK-1775, a potent Wee1 inhibitor, synergizes with gemcitabine to achieve tumor regressions, selectively in p53-deficient pancreatic cancer xenografts.
abstract: OBJECTIVE
  Investigate the efficacy and pharmacodynamic effects of MK-1775, a potent Wee1 inhibitor, in both monotherapy and in combination with gemcitabine (GEM) using a panel of p53-deficient and p53 wild-type human pancreatic cancer xenografts.
  
  
  METHODS
  Nine individual patient-derived pancreatic cancer xenografts (6 with p53-deficient and 3 with p53 wild-type status) from the PancXenoBank collection at Johns Hopkins were treated with MK-1775, GEM, or GEM followed 24 hour later by MK-1775, for 4 weeks. Tumor growth rate/regressions were calculated on day 28. Target modulation was assessed by Western blotting and immunohistochemistry.
  
  
  RESULTS
  MK-1775 treatment led to the inhibition of Wee1 kinase and reduced inhibitory phosphorylation of its substrate Cdc2. MK-1775, when dosed with GEM, abrogated the checkpoint arrest to promote mitotic entry and facilitated tumor cell death as compared to control and GEM-treated tumors. MK-1775 monotherapy did not induce tumor regressions. However, the combination of GEM with MK-1775 produced robust antitumor activity and remarkably enhanced tumor regression response (4.01-fold) compared to GEM treatment in p53-deficient tumors. Tumor regrowth curves plotted after the drug treatment period suggest that the effect of the combination therapy is longer-lasting than that of GEM. None of the agents produced tumor regressions in p53 wild-type xenografts.
  
  
  CONCLUSIONS
  These results indicate that MK-1775 selectively synergizes with GEM to achieve tumor regressions, selectively in p53-deficient pancreatic cancer xenografts.
authors.affiliation: Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. rnv1@jhmi.edu
authors.forename: N V
authors.initials: NV
authors.lastname: Rajeshkumar
authors.forename: Elizabeth
authors.initials: E
authors.lastname: De Oliveira
authors.forename: Niki
authors.initials: N
authors.lastname: Ottenhof
authors.forename: James
authors.initials: J
authors.lastname: Watters
authors.forename: David
authors.initials: D
authors.lastname: Brooks
authors.forename: Tim
authors.initials: T
authors.lastname: Demuth
authors.forename: Stuart D
authors.initials: SD
authors.lastname: Shumway
authors.forename: Shinji
authors.initials: S
authors.lastname: Mizuarai
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Hirai
authors.forename: Anirban
authors.initials: A
authors.lastname: Maitra
authors.forename: Manuel
authors.initials: M
authors.lastname: Hidalgo
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D021441:Carcinoma, Pancreatic Ductal / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors; D045744:Cell Line, Tumor; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D018450:Disease Progression; D004357:Drug Synergism; D005260:Female; D016158:Genes, p53; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009154:Mutation / Q000502:physiology; D009369:Neoplasms / Q000188:drug therapy / Q000473:pathology; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D011720:Pyrazoles / Q000008:administration & dosage* / Q000494:pharmacology; D011743:Pyrimidines / Q000008:administration & dosage* / Q000494:pharmacology; D011744:Pyrimidinones; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays; D000093542:Gemcitabine
chemical_list: D018797:Cell Cycle Proteins; D009687:Nuclear Proteins; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011743:Pyrimidines; D011744:Pyrimidinones; D003841:Deoxycytidine; D011505:Protein-Tyrosine Kinases; C499349:WEE1 protein, human; C549567:adavosertib; D000093542:Gemcitabine